(1)Uganda’s Ebola outbreak challenges vaccine testing
Public health officials had called for African stockpiles of experimental vaccines to speed up responses in future after the latest outbreak of this deadly disease, which started in Uganda during September this year.
Last week, the first piece of good news from the country was that the last known patient had recovered and been discharged from hospital. Health officials hoped that this signals that the spread of the virus has slowed dramatically, if not stopped altogether. Yet the aggressive containment efforts that led to the waning of the outbreak also means a quickly arranged trial of experimental ebolavirus vaccines faces formidable hurdles with potential participants dwindling fast.
The Planned Trial
Scientists plan to start a trial for testing vaccines as soon as possible, but with the problems it had encountered, it may have to be called off. With Ugandan scientists close to the trial and the latest outbreak refusing to discuss sensitive issues and the lack of $9 million in funding, this may never materialise and non-profit American organisations had been left in the air.
Regarded as the worst epidemic in West Africa between 2013 and 2016, Ebola then killed more than 11,300 people. According to the World Health Organization (WHO), as of 25 November this year, Uganda had 141 confirmed cases, 55 of whom had died, including another 22 deaths likely due to the virus, which had spread to Kampala, the heavily populated capital. Mubende and Kassanda districts were the hardest hit.
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The last confirmed case was diagnosed on 13 November. After 42 days have passed without a case, the outbreak officially would have ended. But epidemiologist, Mike Ryan, director of WHO’s Health Emergencies Programme, cautioned a press conference last week that there were still “significant gaps in tracing some of the chains of transmission.” This means new cases and their contacts may soon surface. “Ebola always has a sting in its tail,” he said.
Researchers had hoped for a chance to test new Ebola vaccines. A vaccine has been approved in 2019 for the Zaire Ebola virus. However, monkey studies suggest the vaccine will not work against the genetically distinct Sudan Ebola virus behind this outbreak.
Vaccines on their way to Africa
When the new Ebola cases surfaced, several vaccines for this strain were in development and Ugandan health officials, on 2 December, approved testing three. But, at the start of the outbreak, no manufacturer had enough doses in vials to ship. Doses of vaccines developed by non-profit, Sabin Vaccine Institute and separately by the University of Oxford may arrive in Uganda soon.
The vaccines may arrive too late to assess their worth, however. To be eligible for the ring trial, participants must have been exposed to an infected person within 21 days. As of last week, only a few hundred people remained eligible.
Ana Maria Henao-Restrepo, WHO’s main representative helping to organise the study, said at last week’s press conference the trial was “imminent” but had no set launch date.
Even if the ring trial doesn’t launch, it is hoped that Uganda will stage a phase 1 safety study of the IAVI/Merck vaccine, most likely in health care workers. If it triggers immune responses mirroring those seen with the successful Zaire Ebola virus vaccine, the new data, combined with studies, could persuade regulators to approve it for use in future outbreaks.
The Uganda outbreak highlights the need for a more streamlined outbreak response system. “People got these doses together really, really quickly,” says Nicole Lurie, U.S. director for the Coalition for Epidemic Preparedness Innovations, but perhaps not fast enough to save lives. “We need a reserve of investigational vaccines so they’ll be at the ready for the next outbreak,” she says.
One answer, says Seth Berkley, CEO of Gavi, the Vaccine Alliance, is to stockpile experimental vaccines on the continent for Ebola and other emerging diseases and agree on trial protocols ahead of time. Berkley acknowledges that creating and maintaining stockpiles would cost money and it also means periodically throwing away expiring vaccines and replacing them.
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(2)Antibody against malaria shows promise in Africa
While Ugandan scientists are battling the Sudan Ebola virus, a new antibody against malaria shows promise on the continent. In a first real-world test, parasite-targeting monoclonal antibodies, which have been effective in the lab, protected people in Mali from infections.
Nine volunteers from the United States were deliberately exposed to parasite-laden mosquitoes last year. A study published today in The New England Journal of Medicine (NEJM) showed a single dose of lab-produced monoclonal antibodies can protect recipients from infection for up to six months during Mali’s intense malaria season.
Monoclonal antibodies are expensive to produce and can be cumbersome to administer if infused straight into the bloodstream. This leads to some researchers being sceptical that the new ones to thwart malaria will be of much use except to protect travellers from high-income, non-endemic countries, who often take tablets to prevent parasitic infection transmitted by mosquitoes. However, the team behind the study is working on an easier way to administer the protective proteins and hopes costs will eventually lessen.
It is the first time scientists have brought malaria monoclonal to the field. And it was highly successful,” adds Kirsten Lyke, a vaccinologist at the University of Maryland School of Medicine, who conducted laboratory tests of the antibody.
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The need for new malaria defences is great: In 2020, malaria infected an estimated 241 million people and killed 627,000, 12% more than in 2019. About two-thirds of the deaths were children younger than 5 in Africa. Malaria parasites have developed resistance against many drug and the mosquitoes spreading them have adapted to withstand some insecticides.
A vaccine made by GSK was approved last year by the World Health Organization and is now being rolled out. But it provides mediocre protection and another, developed at the University of Oxford, has yet to show it can provide lasting protection.
A team led by Robert Seder of the U.S. National Institute of Allergy and Infectious Diseases isolated the original antibody from the blood of a person who had received an experimental malaria vaccine in a clinical trial. It binds to the protein studding the surface of the spore like form of the parasite, preventing it from invading liver cells. Researchers tweaked the antibody to prevent it from being too quickly degraded in the human body and mass-produced it in Chinese hamster ovary cells. A “human challenge” study, published last year, found the antibody, given intravenously, prevented infection in all nine volunteers intentionally exposed to the parasite.
The Mali Clinical Trial
In the Mali clinical trial, carried out at the University-of-Sciences-Techniques-and-Technologies-of-Bamako330 volunteers intravenously received a low or high dose of the antibody or a placebo. Their blood was collected and checked for P. falciparum infection at least every two weeks. In the high-dose group, 18% became infected over a period of six months, compared with 36% in the low-dose group and 78% in a placebo group.
By analysing the time to an infection after a person received the monoclonals, scientists found the high dose was 88% effective in preventing infection and the low dose 75%. When analysing the total proportion of participants who were infected in each group by the end of six months, the efficacy fell but still looked promising.
“This will help us to save more lives of children and pregnant women in African countries,” says epidemiologist, Kassoum Kayentao, who presented the findings at the annual meeting of the American Society of Tropical Medicine and Hygiene in Seattle. Kayentao is first author on the NEJM paper.
Faith Osier, a malaria immunologist and vaccinologist from Kenya, at the Imperial College London, calls the paper “hugely exciting.” Still, “I have quite a few ‘yes buts,’” she says. Among them is that infection rates in the study may have been higher than reported because the team used the so-called thick blood smear method to detect parasites, a method that is less sensitive than polymerase chain reaction (PCR) testing. The authors say they are now running PCR analysis on archived specimens.
Even if intravenously delivered monoclonal antibodies prevent disease really well, they have drawbacks, particularly costs, others note. “How much money does it cost to make a monoclonal antibody? Is production cost going to get cheaper and cheaper as the number of antibodies we’re making gets to be bigger and bigger?” asks Myron Cohen, an infectious disease specialist at the Chapel Hill, who has helped develop monoclonal antibodies against HIV and SARS-CoV-2.
Intravenous infusion is also a lengthy procedure, ill-suited to the target population-small children. “There is no 5-year-old who is just going to relax and let you infuse something over half an hour,” Osier says.
A new study already underway in Mali is using subcutaneous injections to test L9LS in children ages 6 to 10. It will measure symptoms, not just infection. A similar trial of L9LS in children ages 5 months to 5 years is also underway in Kenya. As to cost, scientists are hoping increasing yields and potency will eventually make these proteins affordable for use throughout Africa, on par with the cost of malaria vaccines.
Brian Greenwood, a malaria researcher at the London School of Hygiene & Tropical Medicine, sees a place for monoclonal antibodies in the fight against malaria, at least in the short-to-medium term. “A vaccine that gives a high level of protection for several years would be more promising,” Greenwood says—but they don’t exist yet. Until they emerge, he says, monoclonals are “a potentially very valuable new tool.”
